The Laforin-Malin Complex Negatively Regulates Glycogen Synthesis by Modulating Cellular Glucose Uptake via Glucose Transporters

Abstract

Lafora disease (LD), an inherited and fatal neurodegenerative disorder, is characterized by increased cellular glycogen content and the formation of abnormally branched glycogen inclusions, called Lafora bodies, in the affected tissues, including neurons. Therefore, laforin phosphatase and malin ubiquitin E3 ligase, the two proteins that are defective in LD, are thought to regulate glycogen synthesis through an unknown mechanism, the defects in which are likely to underlie some of the symptoms of LD. We show here that laforin's subcellular localization is dependent on the cellular glycogen content and that the stability of laforin is determined by the cellular ATP level, the activity of 5′-AMP-activated protein kinase, and the affinity of malin toward laforin. By using cell and animal models, we further show that the laforin-malin complex regulates cellular glucose uptake by modulating the subcellular localization of glucose transporters; loss of malin or laforin resulted in an increased abundance of glucose transporters in the plasma membrane and therefore excessive glucose uptake. Loss of laforin or malin, however, did not affect glycogen catabolism. Thus, the excessive cellular glucose level appears to be the primary trigger for the abnormally higher levels of cellular glycogen seen in LD.

ACKNOWLEDGMENTS

This work was supported by a sponsored research grant from the Department of Science and Technology, Government of India to S.G. S.G. is a DAE-SRC Outstanding Research Investigator (supported by the Department of Atomic Energy, Government of India) and Joy-Gill Chair Professor. P.S. and S.S received research fellowships from the Council of Scientific and Industrial Research, Government of India.

We thank Kazuhiro Yamakawa (RIKEN Brain Science Institute, Japan) for generously providing muscle tissue samples from laforin-deficient mice, Juan P. Bolanos (Universitario de Salamanca, Spain) for expression constructs for the glucose transporter, Otto Baba (Tokyo Medical and Dental University, Japan) for the glycogen antibody, and Balaji Prakash (IIT Kanpur) for extending the use of his research facilities for some of the experiments reported in the present study. We also thank the anonymous reviewers for their comments and suggestions on an earlier version of this article.